NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Chio, Iok In Christine, Jafarnejad, Seyed Mehdi, Ponz-Sarvise, Mariano, Park, Youngkyu, Rivera, Keith, Palm, Wilhelm, Wilson, John, Sangar, Vineet, Hao, Yuan, Öhlund, Daniel, Wright, Kevin, Filippini, Dea, Lee, Eun Jung, Da Silva, Brandon, Schoepfer, Christina, Wilkinson, John Erby, Buscaglia, Jonathan M, DeNicola, Gina M, Tiriac, Herve, Hammell, Molly, Crawford, Howard C, Schmidt, Edward E, Thompson, Craig B, Pappin, Darryl J, Sonenberg, Nahum, Tuveson, David A (2016) NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell, 166 (4). pp. 963-976. ISSN 0092-8674

URL: http://www.ncbi.nlm.nih.gov/pubmed/27477511
DOI: 10.1016/j.cell.2016.06.056

Abstract

Summary Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA
diseases & disorders > cancer > cancer types > pancreatic cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > translation
CSHL Authors:
Communities: CSHL labs > Hammell M. lab
CSHL labs > Pappin lab
CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 04 Aug 2016 19:46
Last Modified: 07 Oct 2016 19:38
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33150

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